The present invention concerns solid instant-release forms of administration (IR forms of administration) comprising therapeutic agents or concentrates of active substances in particular lipid conjugates of nucleosides which have gel-forming properties in aqueous media. The invention additionally concerns processes for the production of such instant-release forms.
Medicinal substances (active substances) are only used in the rarest cases without being made into a particular form. It is well-known that auxiliary substances can be used to convert them into solid IR forms of administration with conventional galenic processes.
As a rule IR forms of administration should disintegrate very rapidly in order to achieve the required high in vitro dissolution rates of the active substance. The rapid disintegration of the form of administration is determined on the one hand by the selection of the auxiliary substances and of the production process but on the other hand also by the dissolution properties of the active substance itself. The active substances used should usually not form gels or gel-like structures when they dissolve in aqueous media in order to exclude as far as possible a mutual agglutination of the individual particles of active substance.
However, there are also numerous active substances with a lipophilic residue e.g. active substances from the group of lipid conjugates which, when processed to form solid IR forms of administration using conventional galenic processes, tend to form gels or gel-like structures when they dissolve in aqueous media and thus adequately rapid in vitro dissolution rates of the active substance are not achieved. This also applies to blends of active substances which contain the active substance in a high concentration (concentrates of active substances). This disadvantage becomes particularly apparent when monolithic forms of administration (e.g. tablets) in high dosages are desired, the described effect increasing with increasing concentrations of active substance. The in vitro dissolution rate of these formulations and thus also the dissolution rate and resorption rates in vivo are greatly reduced compared to liquid forms of administration.
Within the sense of the invention the term gel-forming active substances is understood to include those active substances which form gel-like phases at concentrations of less than 20% (w/v %) in aqueous systems at 20xc2x0 C. and the solutions resulting therefrom do not exhibit Newtonian flow behaviour. Those fluids are referred to as Newtonian fluids whose flow resistance at a given temperature defined by the Newtonian equation t=hxc2x7D is a material constant in which t is the shear stress, D denotes the velocity gradient and h denotes the dynamic viscosity.
Such active substances and the production thereof are described for example in the applications WO 92/03462, WO 93/16092, WO 93/16091, WO 94/03465, PCT/EP94/02123; DE 4402492, DE 4418690 as well as for example in WO 91/19726, EP 0 350 287, U.S. Pat. Nos. 5,223,263, 5,194,654, 4,921,951, 4,622,392, 4,291,024, 4,283,394. In the case of antivirally active nucleoside derivatives EP 0 350 287 and U.S. Pat. No. 5,223,263 describe lipid derivatives (diacylglycerol nucleosides) and their use in a liposomal form.
The active substances which are frequently also hygroscopic, unstable, incompatible with many common auxiliary substances and have a strong tendency to form gels in aqueous media could not be processed to solid, rapidly disintegrating forms of administration even with the aid of a considerable addition of auxiliary substances. When the active substance-auxiliary substance mixtures or the forms of administration which are produced therefrom are introduced into an aqueous release medium a highly viscous gel layer immediately forms in the boundary phase which makes further rapid dissolution impossible. These gel layers only dissolve very slowly similar to a hydrocolloid matrix and thus have an undesired retarding effect.
Although this retarding effect can be partially compensated by dilution with suitable auxiliary substances, it leads to a tablet size which is not appropriate for the dosage due to the high amounts of auxiliary substances that are required and at higher dosages of active substance monolithic forms of administration can no longer be manufactured.
In addition when the formulation is the same, the in vitro dissolution rate depends on the degree of compaction in the form of administration so that an adequate in vitro dissolution rate was not achievable in the case of compressed forms of administration (e.g. tablets) and also in the case of capsule fillings. In addition tablets produced in this manner often have inadequate hardness and excessive abrasion loss so that high losses occur when producing film coated tablets due to breaking of the tablets in the coating pans used.
The conventional production process leads to a further disadvantage. Due to the dispersion of the active substance in the auxiliary substances required for aqueous granulation, the active substance also comes into contact with incompatible auxiliary substances and thus an adequately high stability of the form of administration can often not be achieved. In addition it was found that the homogeneous distribution of the hygroscopic active substance in the form of administration is not always guaranteed because the particles of active substance rapidly agglomerate to form larger units in the moist medium. However, an inhomogeneous distribution of the active substance in the pharmaceutical mixture with other auxiliary substances is problematic since this can result in different amounts of the active substance in the form of administration when it is processed further to individual dose forms such as tablets or capsules. In addition different lot to lot in vitro dissolution rates of the individual forms of administration resulted within the framework of a technical production of larger amounts which exceeded the usual range of variability despite the same composition of the formulation and the same process steps. However, with regard to the required pharmaceutical safety such risks should be excluded as far as possible when developing pharmaceutical preparations.
For the said reasons it was not possible in the usual manner to arrive at a single form of administration in the desired dosage which has an adequately rapid in vitro dissolution rate using the standard galenic methods of mixing, granulation, spray drying, spray solidification or press granulation of the active substance together with auxiliary substances. Moreover the structure of the granulate adversely affects the stability of the active substance i.e. a satisfactory solution cannot be achieved with conventional methods.
The object of the invention was therefore to develop improved IR forms of administration of active substances or active substance concentrates which form gels in aqueous media.
The object of the invention is achieved by an IR form of administration in which the gel-forming active substances or active substance concentrates are embedded in an envelope which regulates swelling composed of compatible auxiliary substances which inhibit or compensate the gel formation.